Leedham Group: Gastrointestinal Stem Cell Biology Laboratory

01865 287518

Gastrointestinal Stem Cell Biology Laboratory: Bone Morphogenetic Protein signaling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis

The groups interests are in the control and regulation of stem cells in intestinal cancers, and the identification and manipulation of molecular cellular phenotype. The group uses a wide range of human and advanced, disease-positioned mouse models of colorectal cancer to generate multi-omic and spatial biology datasets for integrative analysis.

Tumour heterogeneity plays a key role in cancer adaption and resistance to therapies, but understanding genetic heterogeneity alone cannot paint a complete picture. The forces of natural selection act upon phenotypic characteristics, and phenotype is a function of both the genotype and the microenvironment. The capacity to measure and understand relevant cancer cell phenotypic variation is therefore key to monitoring neoplasia evolutionary trajectory.

In the gut, years of painstaking research have defined reliable molecular markers for bona fide intestinal stem cell populations, and recent work has shown considerable stem cell plasticity in a regenerative setting, with adaptive reprogramming and cellular de-differentiation driven by the disruption of conserved signalling pathways. However, the contribution of stem cell plasticity to tumour development and the neoplastic adaptive response to selective pressures is less well understood. Our lab works to molecularly and morphologically assess stem cell phenotypic heterogeneity in intestinal tumours, use this as a readout to assess mutant epithelial/microenvironmental crosstalk and functionally interrogate the impact of therapeutic selective pressures.

In CRC, especially in microsatellite stable disease, the standard-of-care combination therapies predominantly target the proliferating cancer epithelium alone, and have not advanced significantly for decades, despite huge leaps forward in our understanding of CRC biology. Treatment failure is frequently a consequence of dynamic tumour adaption to therapy, a key phenotypic shift that we are currently unable to reliably assess. Our work proposes that the cancer stem cell molecular phenotype is an informative, and currently unmeasured, readout of dynamic evolutionary change within a tumour, and is an important and clinically translatable metric that can improve prediction of tumour response to treatments, biologically inform existing therapy scheduling and drive the development of new cancer cell adaption drug targets.

Our previous work has shown that genetic predisposition influences BMP/Grem1 signaling and that this can affect the cell-of-origin of resultant tumours. Our work now focuses on the role of microenvironmental (stromal) cell signaling in wound repair and carcinogenesis and investigates whether epithelial somatic mutation spectra can be used translationally, to reflect variable underlying disease pathogenesis.

We currently are working on CRUK funded programme “Stem cells and adaptive molecular phenotype in colorectal cancer (STAMP-CRC)” which seeks to explore the impact of therapeutic selective pressures on stem cell molecular phenotype and target the pathways that enable the rapid evolution of drug resistance

Our research aims to

Investigate mutant epithelium/microenvironmental crosstalk by assessing mutation-induced microenvironmental landscaping.
Functionally interrogate the signalling that regulates cell plasticity and assess the impact of therapeutic selective pressures on stem cell phenotype.
Assess the invasive, engraftment and colonisation capacity of disseminating stem cells and the sculpting of the metastatic niche in secondary host organs.