bioRxiv ScienceSearch

bioRxiv · 10.1101/022491

Gibbs Free Energy of Protein-Protein Interactions Reflects Tumor Stage

Abstract

The sequential changes occurring with cancer progression are now being harnessed with therapeutic intent. Yet, there is no understanding of the chemical thermodynamics of proteomic changes associated with cancer progression/cancer stage. This manuscript reveals a strong correlation of a chemical thermodynamic measure (known as Gibbs free energy) of protein-protein interaction networks for several cancer types and 5-year overall survival and stage in patients with cancer. Earlier studies have linked degree entropy of signaling networks to patient survival data, but not with stage. It appears that Gibbs free energy is a more general metric and accounts better for the underlying energetic landscape of protein expression in cells, thus correlating with stage as well as survival.\n\nThis is an especially timely finding because of improved ability to obtain and analyze genomic/proteomic information from individual patients. Yet, at least at present, only candidate gene imaging (FISH or immunohistochemistry) can be used for entropy computations. With continually expanding use of genomic information in clinical medicine, there is an ever-increasing need to understand the thermodynamics of protein-protein interaction networks.

Explore related subjects

Keep this discovery

BibTeXRIS

Edward Rietman, Alex Bloemendal, John Platig, Jack Tuszynski, Giannoula Lakka Klement. 2015-07-13. Gibbs Free Energy of Protein-Protein Interactions Reflects Tumor Stage. https://doi.org/10.1101/022491

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

A molecular portrait of microsatellite instability across multiple cancers

Microsatellite instability (MSI) refers to the hypermutability of the cancer genome due to impaired DNA mismatch repair. Although MSI has been studied for decades, the large amount of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyze ~8000 exome and ~1000 whole-genome pairs across 23 cancer types. Our pan-cancer analysis reveals that the prevalence of MSI events is highly variable within and across tumor types including some in which MSI is not typically examined. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI events. Finally, we propose an exomebased predictive model for the MSI phenotype that achieves high sensitivity and specificity. These results advance our understanding of the genomic drivers and consequences of MSI, and a comprehensive catalog of tumor-type specific MSI loci we have generated enables efficient panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.

Cancer Biology

Reduced CREB3L2 expression is associated with resistance to sorafenib and poor prognosis in ER-positive breast cancer

Sorafenib is a multikinase inhibitor that acts by inhibiting tumour growth and disrupting tumour microvasculature through anti-proliferative, anti-angiogenic, and pro-apoptotic effects. However, development of resistance to sorafenib often prevents its long-term efficacy. No validated biomarkers currently exist for appropriately selecting patients with cancer for sorafenib treatment. In the present study, we report that CREB3L2 expression in human breast cancer cell lines is a marker of response to sorafenib. Analysis of human breast cancer cell lines using Oncomine database and Genomics of Drug Sensitivity in Cancer (GDSC) database revealed an association between reduced expression of CREB3L2 and sensitivity to sorafenib. Wet lab experiment in five human breast cancer cell lines confirmed the association between reduced expression of CREB3L2 and sensitivity to sorafenib. Further, reduced expression of CREB3L2 was associated with poor Reccurence Free Survival in Luminal breast cancer. Our results suggest that CREB3L2 expression is a biomarker of response to sorafenib and outcome in breast cancer.

Cancer Biology

A Hypothesis to Explain Cancers in Confined Colonies of Naked Mole Rats

Naked mole rats (NMRs) are subterranean eusocial mammals, known for their virtual absence of aging in their first 20 to 30 years of life, and their apparent resistance to cancer development. As such, this species has become an important biological model for investigating the physiological and molecular mechanisms behind cancer resistance. Two recent studies have discovered middle and late-aged worker (that is, non-breeding) NMRs in captive populations exhibiting neoplasms, consistent with cancer development, challenging the claim that NMRs are cancer resistant. These cases are possibly artefacts of inbreeding or certain rearing conditions in captivity, but they are also consistent with evolutionary theory.\n\nWe present field data showing that worker NMRs live on average for 1 to 2 years. This, together with considerable knowledge about the biology of this species, provides the basis for an evolutionary explanation for why debilitating cancers in NMRs should be rare in captive populations and absent in the wild. Whereas workers are important for maintaining tunnels, colony defence, brood care, and foraging, they are highly vulnerable to predation. However, surviving workers either replace dead breeders, or assume other less active functions whilst preparing for possible dispersal. These countervailing forces (selection resulting in aging due to early-life investments in worker function, and selection for breeder longevity) along with the fact that all breeders derive from the worker morph, can explain the low levels of cancer observed by these recent studies in captive colonies. Because workers in the field typically never reach ages where cancer becomes a risk to performance or mortality, those rare observations of neoplastic growth should be confined to the artificial environments where workers survive to ages rarely if ever occurring in the wild. Thus, we predict that the worker phenotype fortuitously benefits from anti-aging and cancer protection in captive populations.

Cancer Biology