How “the cell-of-origin” influences the genetic and epigenetic events of breast cancer diversity and heterogeneity

Recent work from the Kuperwasser Lab has shown that the differentiation state of the cell-of-origin determines the type of cancer will eventually form. Other recent findings have also provided strong molecular evidence supporting the concept that haploinsufficiency for genes in may be associated with features of malignancy. Using these insights, Kuperwasser Lab is employing various genomic, proteomic and chemical platforms developed by various members of the Raymond and Beverly Sackler Convergence Lab to study the following:

  • Identification of novel breast cancer drivers
  • Identification of novel drivers of metastasis
  • Identification of networks that control cell fate decision and differentiation
  • Determine how the differentiation state of the cell of origin determines the genetic landscape of a cancer

Cellular Plasticity and organogenesis

A major effort in the Kuperwasser Lab is to define the cellular precursors to human breast cancers and uncover how mutations or stable epigenetic changes sustained in these cells affect cell fate decisions and cellular plasticity to create heterogeneous tumor phenotypes. Efforts have been focused on uncovering the transcriptional mediators for somatic cell plasticity including transcription factors, chromatin modifiers as well as factors that post-translationally modify these factors (eg. SLUG/SNAI2, TAZ/WWTR1,TBX3 etc). This work has revealed fundamental mechanisms that regulate normal and cancer stem-like states as well as how these factors might be exploited to contribute to metastasis.

Other ongoing interests and projects relating to this include:

  • Identifying breast tissue hierarchy, stem cells, and factors that control cellular plasticity and tissue development
  • How mutations reprogram cell identity
  • Understanding the effects of aging on stem cell fitness
  • Reconstructing human breast tissues in vivo

Stroma in development and disease

The Kuperwasser Lab is working towards identifying and understanding how normal breast stem cells, as well as breast cancer stem cells interact with the host cells during cancer formation, expansion and metastasis. Currently the lab is defining how stromal rigidity due to fibroblast activation affects the recruitment and stimulation of immune cells, which likely participate in cancer development and progression. In addition, the lab is examining how adipocytes in the obese state participate as tumor promoters or suppressors. For these studies they have developed and are utilizing various novel human breast xenograft model systems as well as complementary in vitro co-cultures and 3D culture systems to identify molecular pathways that mediate the complex interactions during the various aspects of normal and neoplastic breast development.

Additional interests and projects are:

  • Understanding the role of adipose stromal cells in cancer initiation
  • Defining how changes in mechanotransduction affect development and disease
  • Eludicadating the molecular mechanisms of microcalcification formation in disease
  • Defining the role of stromal cells in the development of cancer in high risk patients