Biology subjects

Maxwell, C. A.

Publications and source records attributed to Maxwell, C. A..

4 recordsLinked to original sources

bioRxiv2026

A human transcriptomic deletion links cortical expansion and cancer

Alternative splicing represents a major source of potential evolutionary novelty in protein sequence. Despite this, relatively few studies have investigated the functional impacts of human-specific alternative splicing. Here, we analyze RNA-sequencing data from nine iPSC-derived cell types and identify dozens of human transcriptomic conserved deletions (htCONDELs): evolutionary divergence in splicing that leads to the partial or full removal of conserved protein-coding sequence from the human transcriptome. We investigated one example in detail: an htCONDEL in the gene HMMR, which encodes a centrosomal protein that binds microtubules and regulates mitosis. We found that this htCONDEL, which produces a human-specific isoform lacking a conserved microtubule-binding domain, enables cells to flexibly divide with a broader range of mitotic spindle orientations in vitro. Introducing the human HMMR isoform into mice similarly alters the orientation of cell division in the developing neocortex and increases the production of outer radial glia-like cells, the expansion of which played an essential role in increasing human brain size. Combined with previous work implicating the same HMMR isoform in carcinoma progression, our results suggest that evolution of HMMR splicing in humans increased plasticity in cell division, potentially leading to tradeoffs between advantageous effects on brain development and deleterious effects on cancer risk later in life.

evolutionary biology↗

bioRxiv2026

Aurora kinase A enables collective invasion and metastasis by endowing a leader cell phenotype and stabilizing Eplin-mediated cohesion with follower cells

The metastatic process initiates with collective cell invasion into surrounding tissues and axillary nodes, and subsequent colonization at a distant site. Previously, we found collective invasion is augmented during the G2 cell cycle phase, facilitated through Aurora kinase A (AURKA)-mediated centrosome polarization in the leader cell. Here, we identify cell cycle-associated gene signatures as overrepresented in axilla and liver metastatic sites, with AURKA expression strongly correlated with breast cancer metastasis signatures, and pan-cancer patient survival. Then, we show GFP-AURKA expression endows breast epithelia cells with the ability to form metastatic outgrowths within immune-incompetent chicken embryos. Multi-parametric imaging of wound closure assays reveals phenotypes enabled by, and dependent upon AURKA expression. We discover leader cells express AURKA and acquire front-polarized centrosomes, which differentiates them from other cells in the migrating group. Ectopic expression of GFP-AURKA induces a leader cell phenotype. Conversely, inhibition of AURKA activity alters actin dynamics, promotes turnover of cell contacts, and reduces coordination within migrating groups. Specifically, AURKA interacts with the actin regulator EPLIN, and AURKA inhibition localizes EPLIN to lamellipodia and away from E-cadherin-positive contacts. Inhibiting these necessary roles for AURKA may provide a critical barrier against the metastatic spread of human breast carcinoma cells.

cancer biology↗

bioRxiv2019

PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways

Murine xenografts of pediatric leukemia are known to accurately recapitulate genomic aberrations. How this translates to the functional capacity of the proteome is unknown. Here, we studied global protein abundance, phosphorylation, and proteolytic processing in 11 pediatric B- and T-cell acute lymphoblastic leukemia patients and 19 corresponding xenografts. Protein level differences that stratified pediatric disease subtypes at diagnostic and relapse stages were largely recapitulated in xenograft models. Patient xenografts lacked multiple human leukocyte antigens, and complement proteins, and presented incomplete response mechanisms to the host immune system which is absent in the murine model. The dominant expression of MKI67 and cell cycle proteins indicated a high proliferative capacity of xenografted cells residing in the spleen. Structural genomic changes and mutations found in patients were reflected at the protein level. The post-translational modification landscape is shaped by leukemia type and host and only to a limited degree by the patient of origin. This study portrays how genomic and host factors shape protein and post-translational modification landscapes differently, and confirms murine patient-derived xenograft as competent model system while highlighting important areas of diverging biology.

cancer biology↗

bioRxiv2018

FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning

The concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well-established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle-positioning and timely cell division. CK1 is recruited to the spindle by FAM83D, and cells devoid of FAM83D, or those harbouring CK1-binding-deficient FAM83DF283A/F283A knockin mutation, display pronounced spindle-positioning defects, and a prolonged mitosis. Restoring FAM83D at the endogenous locus in FAM83D-/- cells, or artificially delivering CK1 to the spindle in FAM83DF283A/F283A cells, rescues these defects. These findings implicate CK1 as new mitotic kinase that orchestrates the kinetics and orientation of cell division.

cell biology↗