Wong, S. Q. R. | Search bioRxiv

bioRxiv2024

Modelling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype

Drug resistance and distant metastases are major contributors to mortality in colorectal cancer (CRC). Here we investigate mechanisms underlying acquired resistance to oxaliplatin, a first-line, standard-of-care CRC treatment. We generated oxaliplatin-resistant CRC tumor cells with clinically relevant dosing regimen, which displayed enhanced metastatic potential. Transcriptomic and phenotypic analyses revealed a critical function for cholesterol biogenesis in modulating TGF-{beta} signaling activity, which in turn regulates SERPINE1 expression, a gene we identified as a key player in promoting drug resistance and metastasis. Additionally, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that can predict overall and relapse-free survival (RFS) in clinical cohorts and is able to stratify patients into CMS4/iCMS3-fibrotic CRC-subtypes, underscoring its clinical utility. Using mouse tumor models, we provide further evidence that targeting SERPINE1 and cholesterol biogenesis can be viable approaches to re-sensitize the resistant pro-metastatic CRC cells to oxaliplatin. This study not only elucidates the molecular underpinnings of drug resistance and metastasis in primary CRC, but also offers prognostic and therapeutic strategies to guide clinical management of the disease. SignificanceThis study reveals critical resources and insights on oxaliplatin resistance and metastasis in CRC via a novel TGF-{beta} cholesterol axis. We generated improved oxaliplatin-resistant models that enabled identification of a prognostic SERPINE1-based gene signature to predict oxaliplatin resistance-induced metastasis in CRC. This gene signature derived from our models showed that the models can mimic CMS-4/iCMS-fibrotic-like metastatic CRC patients. We validated therapeutic candidates targeting CMS-4/iCMS-fibrotic-like metastatic CRC cells which can reverse drug resistance and metastasis.

cancer biology↗

bioRxiv2019

The chromatin structuring protein HMGA2 influences human subtelomere stability and cancer chemosensitivity

The transient build-up of DNA supercoiling during the translocation of replication forks threatens genome stability and is controlled by DNA topoisomerases (TOPs). This crucial process has been exploited with TOP poisons for cancer chemotherapy. However, pinpointing cellular determinants of the best clinical response to TOP poisons still remains enigmatic. Here, we present an integrated approach and demonstrate that endogenous and exogenous expression of the oncofetal high-mobility group AT-hook 2 (HMGA2) protein exhibited broad protection against the formation of hydroxyurea-induced DNA breaks in various cancer cells, thus corroborating our previously proposed model in which HMGA2 functions as a replication fork chaperone that forms a protective DNA scaffold at or close to stalled replication forks. We now further demonstrate that high levels of HMGA2 also protected cancer cells against DNA breaks triggered by the clinically important TOP1 poison irinotecan. This protection is most likely due to the recently identified DNA supercoil constraining function of HMGA2 in combination with exclusion of TOP1 from binding to supercoiled substrate DNA. In contrast, low to moderate HMGA2 protein levels surprisingly potentiated the formation of irinotecan-induced genotoxic covalent TOP1-DNA cleavage complexes. Our data from cell-based and several in vitro assays indicate that, mechanistically, this potentiating role involves enhanced drug-target interactions mediated by HMGA2 in ternary complexes with supercoiled DNA. Subtelomeric regions were found to be extraordinarily vulnerable to these genotoxic challenges induced by TOP1 poisoning, pointing at strong DNA topological barriers located at human telomeres. These findings were corroborated by an increased irinotecan sensitivity of patient-derived xenografts of colorectal cancers exhibiting low to moderate HMGA2 levels. Collectively, we uncovered a therapeutically important control mechanism of transient changes in chromosomal DNA topology that ultimately leads to enhanced human subtelomere stability. Author SummaryDNA replication fork stability in rapidly dividing cancer cells is of utmost importance for the maintenance of genome stability and cancer cell viability. Cancer cells efficiently prevent fork collapse into lethal double strand breaks as a first line of defense during replication stress, but the corresponding protective mechanisms often remain elusive. Uncontrolled high levels of DNA supercoiling that are generally regulated by topoisomerases can cause replication stress and are major threats to fork stability. Using a multidisciplinary approach, we identified a possible regulatory mechanism of replication stress, which appears to involve mitigating the consequences of DNA topological changes by the oncofetal replication fork chaperone HMGA2. Our work provides mechanistic insights into the control of DNA damage triggered by clinically important anti-cancer drugs, which is mediated by the replication fork chaperone HMGA2. We thereby also identify HMGA2 expression as a predictive therapeutic marker, which could allow clinicians to take informed decisions to prevent tumor recurrence and improve survival.

cancer biology↗