bims-instec 2023-05-07 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2023–05–07
six papers selected by
Maria-Virginia Giolito, Free University of Brussels

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.
Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Colorectal Cancer Prognosis.
Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer.
Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164.
Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study.
APC-driven actin nucleation powers collective cell dynamics in colorectal cancer cells.

ESMO Open. 2023 Apr 26. pii: S2059-7029(23)00420-9. [Epub ahead of print]8(3): 101198

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

G Martini, V Belli, S Napolitano, V Ciaramella, D Ciardiello, A Belli, F Izzo, A Avallone, F Selvaggi, F Menegon Tasselli, W Santaniello, R Franco, I Puig, L Ramirez, I Chicote, F Mancuso, G Caratu, X Serres, R Fasani, J Jimenez, J Ros, I Baraibar, N Mulet, C M Della Corte, T Troiani, A Vivancos, R Dienstmann, E Elez, H G Palmer, J Tabernero, E Martinelli, F Ciardiello, G Argilés.

   BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics.
MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping.
RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy.
CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

Keywords:  3D; PDTO; colorectal cancer; personalized medicine; resistance

DOI:  https://doi.org/10.1016/j.esmoop.2023.101198
Gastroenterology. 2023 May 03. pii: S0016-5085(23)00697-2. [Epub ahead of print]

Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Colorectal Cancer Prognosis.

Linwei Guo, Yunjin Wang, Wenxiao Yang, Chenchen Wang, Tian'an Guo, Jingcheng Yang, Zhiming Shao, Guoxiang Cai, Sanjun Cai, Liying Zhang, Xin Hu, Ye Xu.

   BACKGROUND AND AIMS: Tumor genetic testing is indispensable in the management of primary and metastatic colorectal cancer (mCRC), yet the indications for genomics-guided precision medicine and immunotherapy need to be better understood and defined.
METHODS: We prospectively sequenced tumors from 869 Chinese colorectal cancer patients by a large panel and evaluated the clinical significance of single gene somatic mutations and co-occurring events in mCRC, as well as their functional effects and tumorigenic mechanisms. We systematically assessed the heterogeneity of the tumor immune microenvironment in different genomic contexts through the combined analysis of Immunoscore, multiplex immunostaining, whole-exome sequencing, transcriptome, and single-cell sequencing.
RESULTS: Single-gene somatic mutations in BRAF or RBM10 were associated with shorter progression-free survival (PFS) in mCRC patients. Functional studies suggested RBM10 acts as a tumor suppressor in CRC development. Co-mutations of KRAS/AMER1 or KRAS/APC were enriched in the metastatic cohort, which had poor PFS and did not benefit from bevacizumab due to accelerated drug metabolism. Forty patients (4.6%) carried pathogenic or likely pathogenic germline alterations in the DNA damage repair pathway, and 37.5% of these tumors had secondary-hit events with loss of heterozygosity or biallelic alterations. A high tumor indel burden with MSI-high suggested immunogenicity with numerous activated tumor-infiltrating lymphocytes, whereas POLE-mutation with TMB-ultrahigh indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunological interactions were reflected in the divergent neoantigen presentation and depletion, immune checkpoint expression, PD-1/PD-L1 interaction, and T-cell responsiveness to pembrolizumab.
CONCLUSION: Our integrated analysis provides insights into CRC prognostic stratification, drug response, and personalized genomics-guided targeted and immunotherapies.

Keywords:  Colorectal cancer; Precision therapy; Targeted sequencing

DOI:  https://doi.org/10.1053/j.gastro.2023.04.029
Cell Death Dis. 2023 May 05. 14(5): 306

Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer.

Julia Källberg, Alexandra Harrison, Valerie March, Santa Bērziņa, Ivan Nemazanyy, Oliver Kepp, Guido Kroemer, Sophie Mouillet-Richard, Pierre Laurent-Puig, Valérie Taly, Wenjin Xiao.

The major underlying cause for the high mortality rate in colorectal cancer (CRC) relies on its drug resistance, to which intratumor heterogeneity (ITH) contributes substantially. CRC tumors have been reported to comprise heterogeneous populations of cancer cells that can be grouped into 4 consensus molecular subtypes (CMS). However, the impact of inter-cellular interaction between these cellular states on the emergence of drug resistance and CRC progression remains elusive. Here, we explored the interaction between cell lines belonging to the CMS1 (HCT116 and LoVo) and the CMS4 (SW620 and MDST8) in a 3D coculture model, mimicking the ITH of CRC. The spatial distribution of each cell population showed that CMS1 cells had a preference to grow in the center of cocultured spheroids, while CMS4 cells localized at the periphery, in line with observations in tumors from CRC patients. Cocultures of CMS1 and CMS4 cells did not alter cell growth, but significantly sustained the survival of both CMS1 and CMS4 cells in response to the front-line chemotherapeutic agent 5-fluorouracil (5-FU). Mechanistically, the secretome of CMS1 cells exhibited a remarkable protective effect for CMS4 cells against 5-FU treatment, while promoting cellular invasion. Secreted metabolites may be responsible for these effects, as demonstrated by the existence of 5-FU induced metabolomic shifts, as well as by the experimental transfer of the metabolome between CMS1 and CMS4 cells. Overall, our results suggest that the interplay between CMS1 and CMS4 cells stimulates CRC progression and reduces the efficacy of chemotherapy.

DOI: https://doi.org/10.1038/s41419-023-05806-z
Eur J Cancer. 2023 Feb 24. pii: S0959-8049(23)00108-9. [Epub ahead of print]186 185-195

Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164.

Dung T Le, Luis A Diaz, Tae Won Kim, Eric Van Cutsem, Ravit Geva, Dirk Jäger, Hiroki Hara, Matthew Burge, Bert H O'Neil, Petr Kavan, Takayuki Yoshino, Rosine Guimbaud, Hiroya Taniguchi, Elena Élez, Salah-Eddin Al-Batran, Patrick M Boland, Yi Cui, Pierre Leconte, Patricia Marinello, Thierry André.

   BACKGROUND: Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented.
METHODS: Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability.
RESULTS: Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%-46.0%) in cohort A and 34.9% (95% CI, 23.3%-48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response.
CONCLUSIONS: Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC.
CLINICAL TRIAL REGISTRY INFORMATION: ClinicalTrials.gov, NCT02460198.

Keywords:  Colorectal cancer; Microsatellite instability; Mismatch repair; Pembrolizumab

DOI:  https://doi.org/10.1016/j.ejca.2023.02.016
J Exp Clin Cancer Res. 2023 May 05. 42(1): 115

Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study.

Lars Henrik Jensen, Silvia Regina Rogatto, Jan Lindebjerg, Birgitte Havelund, Cecilie Abildgaard, Luisa Matos do Canto, Chris Vagn-Hansen, Claus Dam, Søren Rafaelsen, Torben Frøstrup Hansen.

   BACKGROUND: Patients with colorectal metastatic disease have a poor prognosis, limited therapeutic options, and frequent development of resistance. Strategies based on tumor-derived organoids are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. Here, we evaluated the method's feasibility and clinical outcome as applied to patients with no satisfactory treatment options.
METHODS: In this phase 2, single-center, open-label, non-comparative study (ClinicalTrials.gov, register NCT03251612), we enrolled 90 patients with metastatic colorectal cancer following progression on or after standard therapy. Participants were 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ function, and metastasis available for biopsy. Biopsies from the metastatic site were cultured using organoids model. Sensitivity testing was performed with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the proportion of patients alive without disease progression at two months per local assessment.
RESULTS: Biopsies available from 82 to 90 patients were processed for cell culture, of which 44 successfully generated organoids with at least one treatment suggested. The precision cohort of 34 patients started treatment and the primary endpoint, progression-free survival (PFS) at two months was met in 17 patients (50%, 95% CI 32-68), exceeding the pre-defined level (14 of 45; 31%). The median PFS was 67 days (95% CI 51-108), and the median overall survival was 189 days (95% CI 103-277).
CONCLUSIONS: Patient-derived organoids and in-vitro sensitivity testing were feasible in a cohort of metastatic colorectal cancer. The primary endpoint was met, as half of the patients were without progression at two months. Cancer patients may benefit from functional testing using tumor-derived organoids.
TRIAL REGISTRATION: ClinicalTrials.gov, register NCT03251612.

Keywords:  Drug screening; Historical controlled phase II trial; Metastatic colorectal cancer; Tumor-derived organoids

DOI:  https://doi.org/10.1186/s13046-023-02683-4
iScience. 2023 May 19. 26(5): 106583

APC-driven actin nucleation powers collective cell dynamics in colorectal cancer cells.

Lautaro Baro, Asifa Islam, Hannah M Brown, Zoë A Bell, M Angeles Juanes.

  Cell remodeling relies on dynamic rearrangements of cell contacts powered by the actin cytoskeleton. The tumor suppressor adenomatous polyposis coli (APC) nucleate actin filaments (F-actin) and localizes at cell junctions. Whether APC-driven actin nucleation acts in cell junction remodeling remains unknown. By combining bioimaging and genetic tools with artificial intelligence algorithms applied to colorectal cancer cell, we found that the APC-dependent actin pool contributes to sustaining levels of F-actin, as well as E-cadherin and occludin protein levels at cell junctions. Moreover, this activity preserved cell junction length and angle, as well as vertex motion and integrity. Loss of this F-actin pool led to larger cells with slow and random cell movement within a sheet. Our findings suggest that APC-driven actin nucleation promotes cell junction integrity and dynamics to facilitate collective cell remodeling and motility. This offers a new perspective to explore the relevance of APC-driven cytoskeletal function in gut morphogenesis.

Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2023.106583