Abstract
Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models. From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis. This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance. This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients.
Highlights
This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of colorectal cancer (CRC)
After surgery (1 hour after resection in average, except for rectal tumors for which it can go up to 4 hours), 2 fragments were snap frozen in liquid nitrogen, stored at À80C, for molecular characterization, 2 fragments were fixed in alcohol-formalin-acetic acid solution and paraffin-embedded for histopathologic analysis, and 2 fragments were transferred in culture medium including DMEM with 10 mmol/L HEPES, 4.5 g/L glucose, 1 mmol/L pyruvate sodium, 200 U/mL penicillin, 200 mg/mL streptomycin, 200 mg/mL gentamicin, 5 mg/mL ciprofloxacin, 20 mg/mL metronidazole, 25 mg/mL vancomycin, and 2.5 mg/mL fungizone or DMEM with Nanomycopulitine (Abcys) for engraftment done in the 24 hours after resection
A total of 85 CRC samples from primary tumors, peritoneal carcinoses, or distant metastases were collected from unsupervised patients and subcutaneously engrafted into nude mice
Summary
This is linked to the natural history of the tumors and/or patients, considering (i) the interpatient variability in drug exposure, (ii) the diversity of CRC with respect to molecular profile and sensitivity to a specific agent, and (iii) the intratumoral heterogeneity, and the highly variable tumor cell doubling time. The interest of patient-derived xenograft (PDX) models in preclinical testing is more and more emphasized These xenografts derived directly from patient samples, without in vitro manipulation, provide a more accurate depiction of human tumor biologic characteristics than cell linederived xenografts with hundreds in vitro passages and serial passing across several generations of mice [1]. As these models might better reflect a clinical response [2,3,4,5,6,7,8], several groups have established diseasespecific panels of xenografts directly from patient tumors
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