Biology subjects

Martins, C. P.

Publications and source records attributed to Martins, C. P..

3 recordsLinked to original sources

bioRxiv2026

Mutant KRAS dosage contributes to heterogeneity in lung cancer therapeutic response

Oncogenic KRAS mutations promote tumorigenesis by constitutive activation of multiple, well-characterised signalling pathways. However, there is significant heterogeneity across mutant KRAS tumours in terms of mutation present, mutant allele abundance and downstream signalling strength. It is unclear whether these variations can impact responses to specific therapies. Here, we demonstrate that [~]20% of lung adenocarcinomas (LUAD) show an increase in mutant KRAS dosage (KRASmutant allele fraction > KRASwild-type). Furthermore, we show that KRAS mutant dosage can directly influence clinical outcome and therapeutic susceptibilities in lung cancer. Our findings show that mutant KRAS copy gains specifically affect platinum lung cancer response, promoting resistance to this standard-of-care therapy. Importantly, increases in KRAS mutant dosage are also associated with an increased vulnerability to pS6K inhibition, due to the unique metabolic rewiring of these cells. Together, we show that mutant KRAS dosage contributes to the phenotypic heterogeneity of mutant KRAS NSCLC and that assessment of mutant KRAS content or signalling strength can help optimise treatments strategies for these patients.

cancer biology↗

bioRxiv2020

ObLiGaRe doxycycline Inducible (ODIn) Cas9 system driving pre-clinical drug discovery, from design to cancer treatment

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. We have generated a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene. Targeted ObLiGaRe resulted in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse can be utilized for robust and tunable genome editing allowing for flexibility, speed and uniformity at reduced cost, leading to high throughput and practical preclinical in vivo therapeutic testing.

genomics↗

bioRxiv2020

Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth

Tumors are comprised of cancer cells and a network of non-cancerous stromal cells. Cancer-associated fibroblasts (CAFs) are well known to support tumorigenesis and are emerging as immune modulators. While many leukocyte populations are well studied in cancer, neutrophils have received less attention. Neutrophils can release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NETs) in a process termed NETosis. Here, we show that CAFs induce formation of NETs both within the tumor microenvironment and at systemic levels in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on PAD4 and CD11b. Remarkably, CAF-derived Amyloid {beta} was identified as the key factor driving t-NETosis, a protein with significance in both neurodegenerative and inflammatory disorders. Therapeutic inhibition of NETs in established tumors prevented growth, skewing neutrophils to a pro-inflammatory phenotype. Reciprocally, t-NETs enhanced CAF activation phenotypes. Mirroring murine observations, NETs were detected juxtaposed to CAFs in human melanoma and pancreatic adenocarcinoma, and elevated expression of amyloid and {beta}-Secretase correlated with poor prognosis. In summary, we report the existence of cross-talk between CAFs and neutrophils within the tumour microenvironment whereby CAF-induced t-NETosis supports cancer progression, identifying Amyloid {beta} as the protagonist and potential therapeutic target. SignificanceThis study defines the existence of a pro-tumor immunomodulatory function of the stroma showing the induction of Neutrophil Extracellular Traps through CAF-derived Amyloid {beta}. We term this novel process "Tumor-induced NETosis" (t-NETosis) and propose that therapeutic inhibition of this mechanism, which we observe in human melanoma and pancreatic cancer, has the potential to improve patient outcome.

cancer biology↗